Cancer is a general term frequently used to indicate any of the various types of malignant neoplasms (i.e., abnormal tissue that grows by cellular proliferation more rapidly than normal), most of which invade surrounding tissue, may metastasize to several sites, are likely to recur after attempted removal, and causes death unless adequately treated. Stedman's Medical Dictionary, Williams & Wilkins, Baltimore, Md., 26th ed. 1995. Although a variety of approaches to cancer therapy (e.g., surgical resection, radiotherapy, and chemotherapy) have been available and commonly used for many years, cancer remains one of the leading causes of death in the world. Melanoma is a particularly deadly neoplasm. Often a late sequela of excessive exposure to sun, it is a rapidly growing tumor that metastasizes early and often. Tumor growth leads to weight loss and patients frequently experience depression. Currently, there is no effective treatment for melanoma, and most patients with metastatic disease will die prematurely.
Antidepressants are widely prescribed, not only to treat depression, but also to treat anxiety disorder, obsessive-compulsive disorder, panic, bulimia nervosa and chronic pain. It is estimated that approximately 6% of the general population and 25% of hospitalized cancer patients, who often experience anxiety and pain due to the progression of their disease, are clinically depressed.
Selective serotonin reuptake inhibitors (SSRI) agents are widely used as anti-depressants. This group of compounds includes fluoxetine, sertraline, paroxetine, fluvoxamine and citalopram. It is thought that such compounds act by inhibiting the transport of the neurotransmitter serotonin (5-hydroxytryptamine, 5-HT), thereby increasing the efficacy of neurotransmission. In addition, fluoxetine has been shown to be effective for the treatment of obsessive-compulsive disorder and bulimia nervosa.
Although serotonin is characterized as a neurotransmitter, serotonin transporters have been found in many non-neural cells, including cancer cells. Its function in non-neural cells has not been fully elucidated. However, the widespread distribution of transporters suggests that the effect of serotonergic drugs is pleiotropic and can be considered unpredictable. Medical personnel can be reluctant to prescribe anti-depressants to alleviate major depression or adjustment disorder of cancer patients, because of conflicting reports on the stimulation of cancer growth by anti-depressants. Steingart et al. reviewed the literature published from 1976 to 1993 for reports of human and experimental studies that examined the association of antidepressants with cancer or the effect of antidepressants on neoplastic growth (Steingart et al., J. Clin. Epidemiol., 48, 1407-1412 (1995)). Their search revealed four human studies and nine experimental models reported conflicting results. For example, the widely used antidepressant fluoxetine was reported to be both a tumor promoter and an antineoplastic agent.
Antidepressants are not neoplastic-causing agentsper se, but may directly or indirectly promote or suppress neoplasms once established. For example, tumors contain varying levels of serotonin transporters, the binding to which by serotonin or a serotonin transport inhibitor somehow affects tumor growth. The presence of serotonergic agents may thus have a direct effect on tumor growth. Alternatively, metabolic pathways, e.g., P-450 mixed function monooxygenase system, which activate many antineoplastic drugs may be inhibited or stimulated by SSRIs, modulating the effectiveness of chemotherapeutic agents. Fluoxetine is known to bind to growth-regulatory intracellular histamine receptors and has been shown to inhibit immune function, which tends to permit tumor growth. It is suspected that the conflicting reports of tumor promotion versus suppression cited in the above review may be the result of timing of dosage, level of dosing, effect on the immune system, stage of the disease or specificity of the tumor. In any case, it is apparent that the effect of serotonergic agents is complex and unpredictable. It is necessary in each case to balance carefully the advantages and disadvantages of anti-depressant drugs for cancer patients.
Thus, there is a need to provide the psychological benefits of antidepressant therapy to cancer patients, without interfering with treatment modalities, e.g., chemotherapy, or the potentiation of tumor growth. In addition, there exists a need for effective melanoma therapies.